Gutenberg Open Science

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ZeitschriftenaufsatzAccess status: Open Access ,
Multi-scale simulations of MUT-16 scaffold protein phase separation and client recognition
(2025) Gaurav, Kumar; Busetto, Virginia; Páez-Moscoso, Diego Javier; Changiarath, Arya; Hanson, Sonya M.; Falk, Sebastian; Ketting, René F.; Stelzl, Lukas S.
Phase separation of proteins plays a critical role in cellular organization. How phase-separated protein condensates underpin biological function and how condensates achieve specificity remain elusive. We investigated the phase separation of MUT-16, a scaffold protein in Mutator foci, and its role in recruiting the client protein MUT-8, a key component in RNA silencing in Caenorhabditis elegans. We employed a multi-scale approach that combined coarse-grained (residue-level CALVADOS2 and near-atomistic Martini3) and atomistic simulations. Simulations across different resolutions provide a consistent perspective on how MUT-16 condensates recruit MUT-8, enabling the fine-tuning of chemical details and balancing the computational cost. Both coarse-grained models (CALVADOS2 and Martini3) predicted the relative phase-separation propensities of MUT-16’s disordered regions, which we confirmed through in vitro experiments. Simulations also identified key sequence features and residues driving phase separation and revealed differences in residue interaction propensities between CALVADOS2 and Martini3. Furthermore, Martini3 and 350-μs atomistic simulations on Folding@Home of MUT-8’s N-terminal prion-like domain with MUT-16 M8BR cluster highlighted the importance of cation- interactions between Tyr residues of MUT-8 and Arg residues of MUT-16 M8BR. Lys residues were observed to be more prone to interact in Martini3. Atomistic simulations revealed that the guanidinium group of Arg also engages in - interactions and hydrogen bonds with the backbone of Tyr, possibly contributing to the greater strength of Arg-Tyr interactions compared to Lys-Tyr, where these additional favorable contacts are absent. In agreement with our simulations, in vitro co-expression pull-down experiments demonstrated a progressive loss of MUT-8 recruitment after the mutation of Arg in MUT-16 M8BR to Lys or Ala, confirming the critical role of Arg in this interaction. These findings advance our understanding of MUT-16 phase separation and subsequent MUT-8 recruitment, key processes in assembling Mutator foci that drive RNA silencing in C. elegans. Previous article
ZeitschriftenaufsatzAccess status: Open Access ,
Polyamines regulate adaptive antitumor immunity by functional specialization of regulatory T cells
(2025) Bündgen, Georg; Ulges, Alexander; Pietruschka, Jan; Truong-Andrievici, Natalia; Klein, Matthias; Romaniuk, Karolina; Schmitt, Fabian; Hagen, Mathias; Seebass, Joachim G.; Zezlina, Lenart; Stein, Lara; Probst, Hans Christian; Distler, Ute; Tenzer, Stefan; Lohoff, Michael; Romero-Olmedo, Addi J.; Mei, Henrik; Bohn, Toszka; Delacher, Michael; Schmidlin, Thierry; Gaida, Matthias M.; Dikic, Ivan; Imbusch, Charles; Schild, Hansjörg; Bopp, Tobias
In cancer, metabolic changes and uncontrolled tumor growth alter nutrient availability, impacting antitumor immune responses. Regulatory T (Treg) cells are a subset of T cells with immunosuppressive properties that can also influence tissue homeostasis and repair. However, it is not known how these functions are molecularly controlled and whether they are influenced by tumor metabolism. Here, we report that excessive release of polyamines in the tumor microenvironment directs the functional polarization of Treg cells toward immunosuppression in a protein kinase CK2 (CK2)-dependent manner. Polyamine deprivation as well as genetic or pharmacological inhibition of CK2 activity in Treg cells induced tissue reparative properties in Treg cells that orchestrated efficient antitumor type 2 immune responses and coordinated tissue repair mechanisms to support tumor eradication. These findings suggest that targeted modulation of Treg cell functions could be leveraged as a potential avenue for cancer therapy.
ZeitschriftenaufsatzAccess status: Open Access ,
Patient needs in the context of gynecologic oncology and breast cancer : a validation study
(2025) Theis, Susanne; Frühwein, Hamideh; Hasenburg, Annette; Moehler, Markus; Paul, Norbert W.
Medical advancements and therapeutic innovations are progressing rapidly, necessitating corresponding adaptations in the delivery of patient-centered care. This study explores the needs of women diagnosed with gynecologic and breast cancers, using the frameworks of the National Academy of Medicine and the Picker Institute as reflective lenses. We conducted a qualitative, single-center study employing grounded theory methodology. Semi-structured interviews were carried out with 20 patients undergoing treatment for gynecologic malignancies and breast cancer at a university medical center. Interviews covered multiple phases of illness, including treatment initiation, adaptation, abstention, and future-oriented decisions. Data were analyzed inductively using constant comparative methods. Findings largely affirmed the relevance of the eight established domains of patient-centered care - personal values, clear information and education, emotional support, involvement of family and friends, physical comfort, coordinated care, continuity, and access to treatment. Three additional insights emerged: needs vary according to illness phase and tend to taper over time; they are grounded in ethical dimensions, including social identity, epistemic agency, and moral distress; and they are interdependent, requiring holistic rather than isolated responses. These results highlight that effective patient-centered care must account not only for the content of care but also for its timing, context and ethical significance, warranting integration into standard oncological practice.